Proteomic landscape of epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is a deadly disease with limited diagnostic biomarkers and therapeutic targets. Here we conduct a comprehensive proteomic profiling of ovarian tissue and plasma samples from 813 patients with different histotypes and therapeutic regimens, covering the expression of 10,715 proteins. We identify eight proteins associated with tumor malignancy in the tissue specimens, which are further validated as potential circulating biomarkers in plasma. Targeted proteomics assays are developed for 12 tissue proteins and 7 blood proteins, and machine learning models are constructed to predict one-year recurrence, which are validated in an independent cohort. These findings contribute to the understanding of EOC pathogenesis and provide potential biomarkers for early detection and monitoring of the disease. Additionally, by integrating mutation analysis with proteomic data, we identify multiple proteins related to DNA damage in recurrent resistant tumors, shedding light on the molecular mechanisms underlying treatment resistance. This study provides a multi-histotype proteomic landscape of EOC, advancing our knowledge for improved diagnosis and treatment strategies.

Therapeutic targeting ERRγ suppresses metastasis via extracellular matrix remodeling in small cell lung cancer.

Small-cell lung cancer (SCLC) is the most aggressive and lethal type of lung cancer, characterized by limited treatment options, early and frequent metastasis. However, the determinants of metastasis in SCLC are poorly defined. Here, we show that estrogen-related receptor gamma (ERRγ) is overexpressed in metastatic SCLC tumors, and is positively associated with SCLC progression. ERRγ functions as an essential activator of extracellular matrix (ECM) remodeling and cell adhesion, two critical steps in metastasis, by directly regulating the expression of major genes involved in these processes. Genetic and pharmacological inhibition of ERRγ markedly reduces collagen production, cell-matrix adhesion, microfilament production, and eventually blocks SCLC cell invasion and tumor metastasis. Notably, ERRγ antagonists significantly suppressed tumor growth and metastasis and restored SCLC vulnerability to chemotherapy in multiple cell-derived and patient-derived xenograft models. Taken together, these findings establish ERRγ as an attractive target for metastatic SCLC and provide a potential pharmacological strategy for treating this lethal disease.

Temporal Variations in Fire Impacts on Characteristics and Composition of Soil-Derived Dissolved Organic Matter at Qipan Mountain, China.

Dissolved organic matter (DOM), the most reactive fraction of forest soil organic matter, is increasingly impacted by wildfires worldwide. However, few studies have quantified the temporal changes in soil DOM quantity and quality after fire. Here, soil samples were collected after the Qipan Mountain Fire (3-36 months) from pairs of burned and unburned sites. DOM contents and characteristics were analyzed using carbon quantification and various spectroscopic and spectrometric techniques. Compared with the unburned sites, burned sites showed higher contents of bulk DOM and most DOM components 3 months after the fire but lower contents of them 6-36 months after the fire. During the sharp drop of DOM from 3 to 6 months after the fire, carboxyl-rich alicyclic molecule-like and highly unsaturated compounds had greater losses than condensed aromatics. Notably, the burned sites had consistently higher abundances of oxygen-poor dissolved black nitrogen and fluorescent DOM 3-36 months after the fire, particularly the abundance of pyrogenic C2 (excitation/emission maxima of <250/∼400 nm) that increased by 150% before gradually declining. This study advances the understanding of temporal variations in the effects of fire on different soil DOM components, which is crucial for future postfire environmental management.

Discovery of a Highly Potent Lysine Methyltransferases G9a/NSD2 Dual Inhibitor to Treat Solid Tumors.

Both G9a and NSD2 have been recognized as promising therapeutic targets for cancer treatment. However, G9a inhibitors only showed moderate inhibitory activity against solid tumors and NSD2 inhibitors were limited to the treatment of hematological malignancies. Inspired by the advantages of dual-target inhibitors that show great potential in enhancing efficiency, we developed a series of highly potent G9a/NSD2 dual inhibitors to treat solid tumors. The candidate 16 demonstrated much enhanced antiproliferative activity compared to the selective G9a inhibitor 3 and NSD2 inhibitor 15. In addition, it exhibited superior potency in inhibiting colony formation, inducing cell apoptosis, and blocking cancer cell metastasis. Furthermore, it effectively inhibited the catalytic functions of both G9a and NSD2 in cells and exhibited significant antitumor efficacy in the PANC-1 xenograft model with good safety. Therefore, compound 16 as a highly potent G9a/NSD2 dual inhibitor presents an attractive anticancer drug candidate for the treatment of solid tumors.

Temporal variations in absorption and translocation of heavy metal(loid)s in pak choi (Brassica rapa L.) under open-field and greenhouse cultivation.

Elucidating the absorption and translocation of heavy metal(loid)s by common vegetables across different growth environments and stages is crucial for conducting accurate environmental risk assessments and for associated control. This study investigated temporal variations in the absorption and translocation capacities of pak choi (Brassica rapa L.) for As, Cd, Cr, Cu, Pb, and Zn in polluted soils during the plant growth cycle under greenhouse and open-field cultivation modes. Results showed high root metal(loid) bioconcentration factors and root-to-shoot translocation factors for Cd (0.25 and 1.44, respectively) and Zn (0.26 and 1.01), but low values for As (0.06 and 0.88) and Pb (0.06 and 0.87). The Cd concentration in the aerial edible parts peaked during the early slow growth period, whereas other heavy metal(loid)s peaked during the later stable maturity period. Root bioconcentration and root-to-shoot translocation factors did not significantly differ between cultivation modes. However, greenhouse cultivation exhibited lower average Cd and Zn concentrations in the edible parts and cumulative uptake amounts of most metal(loid)s than open-field cultivation during the typical harvest period spanning days 60 and 90. Short-term transitioning from open-field to greenhouse cultivation may reduce health risks associated with heavy metal(loid) intake via pak choi consumption. These findings facilitate sustainable agricultural practices and food safety management.

Efficacy and safety of vaccines to prevent respiratory syncytial virus infection in infants and older adults: A systematic review and meta-analysis.

OBJECTIVES: To determine the efficacy and safety of respiratory syncytial virus (RSV) vaccines in infants and older adults. METHODS: We performed a systematic review and meta-analysis of randomized control trials that evaluated the efficacy of maternal RSV immunization against infections in infants, as well as the efficacy of RSV vaccines in older adults. The primary outcome was the vaccine efficacy against RSV-related lower respiratory tract disease (LRTD). Grading of Recommendations Assessment, Development and Evaluation criteria was used to evaluate the level of evidence. RESULTS: Ten trials were included in the review. For maternal vaccination, the RSV vaccine showed favourable efficacy against RSV-related LRTD (vaccine efficacy 57.3%, 95% confidence interval [CI] 31.3-73.5; low certainty) and RSV-related severe LRTD (vaccine efficacy 81.9%, 95% CI 56.8-92.4; moderate certainty) in infants within 90 days after birth. For older adults, Meta-analysis showed that RSV vaccines could also reduce the risk of RSV-related LRTD (vaccine efficacy 78.3%, 95% CI 65.6-86.3; moderate certainty) and RSV-related severe LRTD (vaccine efficacy 86.5%, 95% CI 68.3-94.3; moderate certainty). There was no significant difference in serious adverse events between RSV vaccines and placebo. CONCLUSION: RSV vaccines have the potential to offer protection against RSV disease in both infants and older adults, without apparent safety concerns.

Candidate prognostic biomarkers and prediction models for high-grade serous ovarian cancer from urinary proteomics.

High-grade serous ovarian cancer (HGSOC) is one of the most common histologic types of ovarian cancer. The purpose of this study was to identify potential prognostic biomarkers in urine specimens from patients with HGSOC. First, 56 urine samples with information on relapse-free survival (RFS) months were collected and classified into good prognosis (RFS ≥ 12 months) and poor prognosis (RFS < 12 months) groups. Next, data-independent acquisition (DIA)-based mass spectrometry (MS) analysis was combined with MSFragger-DIA workflow to identify potential prognostic biomarkers in a discovery set (n = 31). With the aid of parallel reaction monitoring (PRM) analysis, four candidate biomarkers (ANXA1, G6PI, SPB3, and SPRR3) were finally validated in both the discovery set and an independent validation set (n = 25). Subsequent RFS and Cox regression analyses confirmed the utility of these candidate biomarkers as independent prognostic factors affecting RFS in patients with HGSOC. Regression models were constructed to predict the 12-month RFS rate, with area under the receiver operating characteristic curve (AUC) values ranging from 0.847 to 0.905. Overall, candidate prognostic biomarkers were identified in urine specimens from patients with HGSOC and prediction models for the 12-month RFS rate constructed. SIGNIFICANCE: OC is one of the leading causes of death due to gynecological malignancies. HGSOC constitutes one of the most common histologic types of OC with aggressive characteristics, accounting for the majority of advanced cases. In cases where patients with advanced HGSOC potentially face high risk of unfavorable prognosis or disease advancement within a 12-month period, intensive medical monitoring is necessary. In the era of precision cancer medicine, accurate prediction of prognosis or 12-month RFS rate is critical for distinguishing patient groups requiring heightened surveillance. Patients could significantly benefit from timely modifications to treatment regimens based on the outcomes of clinical monitoring. Urine is an ideal resource for disease surveillance purposes due to its easy accessibility. Furthermore, molecules excreted in urine are less complex and more stable than those in other liquid samples. In the current study, we identified candidate prognostic biomarkers in urine specimens from patients with HGSOC and constructed prediction models for the 12-month RFS rate.

Targeting KPNB1 with genkwadaphnin suppresses gastric cancer progression through the Nur77-mediated signaling pathway.

Gastric cancer (GC) remains a global challenge due to the lack of early detection and precision therapies. Genkwadaphnin (DD1), a natural diterpene isolated from the bud of Flos GenkWa (Thymelaeaceae), serves as a Karyopherin ß1 (KPNB1) inhibitor. In this study, we investigated the anti-tumor effect of DD1 in both cell culture and animal models. Our findings reveal that KPNB1, a protein involved in nuclear import, was highly expressed in GC tissues and associated with a poor prognosis in patients. We demonstrated that DD1, alongside the established KPNB1 inhibitor importazole (IPZ), inhibited GC cell proliferation and tumor growth by enhancing both genomic and non-genomic activity of Nur77. DD1 and IPZ reduced the interaction between KPNB1 and Nur77, resulting in Nur77 cytoplasmic accumulation and triggering mitochondrial apoptosis. The inhibitors also increased the expression of the Nur77 target apoptotic genes ATF3, RB1CC1 and PMAIP1, inducing apoptosis in GC cell. More importantly, loss of Nur77 effectively rescued the inhibitory effect of DD1 and IPZ on GC cells in both in vitro and in vivo experiments. In this study, we for the first time explored the relationship between KPNB1 and Nur77, and found KPNB1 inhibition could significantly increase the expression of Nur77. Moreover, we investigated the function of KPNB1 in GC for the first time, and the results suggested that KPNB1 could be a potential target for cancer therapy, and DD1 might be a prospective therapeutic candidate.

Aridity affects soil organic carbon concentration and chemical stability by different forest types and soil processes across Chinese natural forests.

Forest soils play a critical role in carbon (C) reservoirs and climate change mitigation globally. Exploring the driving factors of soil organic carbon (SOC) concentration and stability in forests on a large spatial scale can help us evaluate the role of forest soils in regulating C sequestration. Based on SOC quantification and solid-state 13C nuclear magnetic resonance spectroscopy, we investigated the SOC concentration and SOC chemical stability (indicated by alkyl-to-O-alkyl ratio and hydrophobic-to-hydrophilic ratio) in top 0-5 and 5-10 cm soils from 65 Chinese natural forest sites and explored their driving factors. Results showed that SOC concentration in 0-5 cm soils were highest in mixed forests but SOC chemical stability in 0-5 cm soils were highest in coniferous forests, while SOC concentration and chemical stability in 5-10 cm soil layers did not differ across forest types. SOC concentration in 0-5 cm was directly related to soil pH and soil bacterial diversity. Structural equation models showed that aridity indirectly affected SOC concentration in 0-5 cm by directly affecting soil pH. While SOC chemical stability in 0-5 cm soils was higher with increased aridity. According to the correlations, the potential mechanisms could be attributed to higher proportion of coniferous forests in more arid forest sites, lower relative abundance of O-alkyl C, higher MgO and CaO contents, and higher bacterial diversity in soils from more arid forest sites. Our study reveals the important role of aridity in mediating SOC concentration and chemical stability in top 0-5 cm soils in Chinese natural forests on a large-scale field investigation. These results will help us better understand the different mechanisms underlying SOC concentration and stability in forests and assess the feedback of forest SOC to future climate change.

Laser regulated mixed-phase TiO2 for electrochemical overall nitrogen fixation.

Traditional oxide electrocatalytic materials encounter significant challenges associated with sluggish reaction kinetics and formidable energy barriers for NH intermediates formation in electrocatalytic nitrogen fixation. The implementation of phase control emerges as an effective strategy to address these challenges. Herein, leveraging the energy localization of laser, this work achieved precise phase control of TiO2. In the optimized material system, the rutile phase TiO2 facilitates nitrogen adsorption, while the anatase phase TiO2 provides proton sources and active oxygen species. The synergistic effect of the two phases effectively enhances the electrocatalytic activity for nitrogen reduction and oxidation, with an ammonia yield reaching âˆ¼22.3 µg h-1 cm-2 and a nitrate yield reaching âˆ¼60.9 µg h-1 cm-2. Furthermore, a coupled dual-electrode system with mixed-phase titanium dioxide as both the anode and cathode successfully achieved a breakthrough in electrochemical overall nitrogen fixation. This laser precision control strategy for manipulating phase sites lays the groundwork for designing efficient catalysts for energy conversion and even energy storage nanomaterials.

Molecular-level carbon traits underlie the multidimensional fine root economics space.

Carbon influences the evolution and functioning of plants and their roots. Previous work examining a small number of commonly measured root traits has revealed a global multidimensionality of the resource economics traits in fine roots considering carbon as primary currency but without considering the diversity of carbon-related traits. To address this knowledge gap, we use data from 66 tree species from a tropical forest to illustrate that root economics space co-varies with a novel molecular-level traits space based on nuclear magnetic resonance. Thinner fine roots exhibit higher proportions of carbohydrates and lower diversity of molecular carbon than thicker roots. Mass-denser fine roots have more lignin and aromatic carbon compounds but less bioactive carbon compounds than lighter roots. Thus, the transition from thin to thick fine roots implies a shift in the root carbon economy from 'do-it-yourself' soil exploration to collaboration with mycorrhizal fungi, while the shift from light to dense fine roots emphasizes a shift from acquisitive to conservative root strategy. We reveal a previously undocumented role of molecular-level carbon traits that potentially undergird the multidimensional root economics space. This finding offers new molecular insight into the diversity of root form and function, which is fundamental to our understanding of plant evolution, species coexistence and adaptations to heterogeneous environments.

Pharmacologic and Nutritional Interventions for Early Alzheimer's Disease: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.

Background: Early intervention is essential for meaningful disease modification in Alzheimer's disease (AD). Objective: We aimed to determine the efficacy and safety of pharmacologic and nutritional interventions for early AD. Methods: PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov were searched from database inception until 1 September 2023. We included randomized controlled trials that evaluated the efficacy of interventions in early AD. Only interventions that demonstrated efficacy compared to placebo were included in the network meta-analysis (NMA). Then we performed frequentist fixed-effects NMA to rank the interventions. GRADE criteria were used to evaluate the level of evidence. Results: Fifty-eight trials including a total of 33,864 participants and 48 interventions were eligible for inclusion. Among the 48 interventions analyzed, only 6 (12.5%) treatments- ranging from low to high certainty- showed significant improvement in cognitive decline compared to placebo. High certainty evidence indicated that donanemab (standardized mean difference [SMD] -0.239, 95% confidence interval [CI] -0.343 to -0.134) and lecanemab (SMD -0.194, 95% CI -0.279 to -0.108) moderately slowed the clinical progression in patients with amyloid pathology. Additionally, methylphenidate, donepezil, LipiDiDiet, and aducanumab with low certainty showed significant improvement in cognitive decline compared to placebo. However, there was no significant difference in serious adverse events as reported between the six interventions and placebo. Conclusions: Only 12.5% of interventions studied demonstrated efficacy in reducing cognitive impairment in early AD. Donanemab and lecanemab have the potential to moderately slow the clinical progression in patients with amyloid pathology. Further evidence is required for early intervention in AD.

Tumor mitochondrial oxidative phosphorylation stimulated by the nuclear receptor RORγ represents an effective therapeutic opportunity in osteosarcoma.

Osteosarcoma (OS) is the most common malignant bone tumor with a poor prognosis. Here, we show that the nuclear receptor RORγ may serve as a potential therapeutic target in OS. OS exhibits a hyperactivated oxidative phosphorylation (OXPHOS) program, which fuels the carbon source to promote tumor progression. We found that RORγ is overexpressed in OS tumors and is linked to hyperactivated OXPHOS. RORγ induces the expression of PGC-1ß and physically interacts with it to activate the OXPHOS program by upregulating the expression of respiratory chain component genes. Inhibition of RORγ strongly inhibits OXPHOS activation, downregulates mitochondrial functions, and increases ROS production, which results in OS cell apoptosis and ferroptosis. RORγ inverse agonists strongly suppressed OS tumor growth and progression and sensitized OS tumors to chemotherapy. Taken together, our results indicate that RORγ is a critical regulator of the OXPHOS program in OS and provides an effective therapeutic strategy for this deadly disease.

Uptake of polycyclic aromatic hydrocarbons (PAHs) from PAH-contaminated soils to carrots and Chinese cabbages under the greenhouse and field conditions.

Polycyclic aromatic hydrocarbons (PAHs) with the properties of structural stability, semi-volatility, and hydrophobicity are toxic and persistent in environments; thus, their transport and fate in agroecosystems is essential for reducing PAH accumulation in the edible parts of crops. Here, we cultivated cabbages (Brassica pekinensis L.) and carrots (Daucus carota L.) in PAH-contaminated soils under the greenhouse and field conditions. After harvesting, we observed a 9.5-46% reduction in soil ∑PAH concentrations. There were 37% of bioconcentration factors (BCFbs) > 1 and 93% of translocation factors (TFab) > 1, while low-molecular-weight (LMW) PAHs had higher BCFbs than high-molecular-weight (HMW) PAHs. The PAH concentrations showed significant and positive correlations among soils, the belowground parts, and the aboveground parts. The toxicity equivalent concentration (TEQBaP) followed the order of cabbage (greenhouse) > cabbage (field) > carrot (greenhouse) > carrot (field), suggesting potentially higher health risks in cabbage relative to carrot and vegetables under the greenhouse relative to field condition. Our study suggested growing carrots under field conditions as a management strategy for reducing the risks of vegetables grown in PAH-contaminated soils.

A ß-Galactosidase-Activated Fluorogenic Reporter for the Detection of Gastric Cancer In Vivo and in Urine.

Although gastric cancer (GC) is one of the most frequent malignant tumors in the digestive tract with high morbidity and mortality, it remains a diagnostic dilemma due to its reliance on invasive biopsy or insensitive assays. Herein, we report a fluorescent gastric cancer reporter (FGCR) with activatable near-infrared fluorescence (NIRF) signals and high renal-clearance efficiency for the detection of orthotopic GC in a murine model via real-time imaging and remote urinalysis. In the presence of gastric-tumor-associated ß-galactosidase (ß-Gal), FGCR can be fluorescently activated for in vivo NIRF imaging. Relying on its high renal-clearance efficiency (∼95% ID), it can be rapidly excreted through kidneys to urine for the ultrasensitive detection of tumors with a diameter down to ∼2.1 mm and for assessing the prognosis of oxaliplatin-based chemotherapy. This study not only provides a new approach for noninvasive auxiliary diagnosis and prognosis of GC but also provides guidelines for the development of fluorescence probes for cancer diagnosis.

Photo-methanification of aquatic dissolved organic matters with different origins under aerobic conditions: Non-negligible role of hydroxyl radicals.

Lingering inconsistencies in the global methane (CH4) budget and ambiguity in CH4 sources and sinks triggered efforts to identify new CH4 formation pathways in natural ecosystems. Herein, we reported a novel mechanism of light-induced generation of hydroxyl radicals (•OH) that drove the production of CH4 from aquatic dissolved organic matters (DOMs) under ambient conditions. A total of five DOM samples with different origins were applied to examine their potential in photo-methanification production under aerobic conditions, presenting a wide range of CH4 production rates from 3.57 × 10-3 to 5.90 × 10-2 nmol CH4 mg-C-1 h-1. Experiments of •OH generator and scavenger indicated that the contribution of •OH to photo-methanificaiton among different DOM samples reached about 4∼42 %. In addition, Fourier transform infrared spectroscopy and Fourier transform ion cyclotron resonance mass spectrometry showed that the carbohydrate- and lipid-like substances containing nitrogen-bonded methyl groups, methyl ester, acetyl groups, and ketones, were the potential precursors for light-induced CH4 production. Based on the experimental results and simulated calculations, the contribution of photo-methanification of aquatic DOMs to the diffusive CH4 flux across the water-air interface in a typical eutrophic shallow lake (e.g., Lake Chaohu) ranged from 0.1 % to 18.3 %. This study provides a new perspective on the pathways of CH4 formation in aquatic ecosystems and a deeper understanding on the sources and sinks of global CH4.

DHODH inhibition represents a therapeutic strategy and improves abiraterone treatment in castration-resistant prostate cancer.

Castration-resistant prostate cancer (CRPC) is an aggressive disease with poor prognosis, and there is an urgent need for more effective therapeutic targets to address this challenge. Here, we showed that dihydroorotate dehydrogenase (DHODH), an enzyme crucial in the pyrimidine biosynthesis pathway, is a promising therapeutic target for CRPC. The transcript levels of DHODH were significantly elevated in prostate tumors and were negatively correlated with the prognosis of patients with prostate cancer. DHODH inhibition effectively suppressed CRPC progression by blocking cell cycle progression and inducing apoptosis. Notably, treatment with DHODH inhibitor BAY2402234 activated androgen biosynthesis signaling in CRPC cells. However, the combination treatment with BAY2402234 and abiraterone decreased intratumoral testosterone levels and induced apoptosis, which inhibited the growth of CWR22Rv1 xenograft tumors and patient-derived xenograft organoids. Taken together, these results establish DHODH as a key player in CRPC and as a potential therapeutic target for advanced prostate cancer.